" this...could put researchers on the royal road to stroke treatment."

Johns Hopkins scientists have identified a new and unusual nerve transmitter in the
brain, one that overturns certain long-cherished laws about how nerve cells behave.

Reporting in the current Proceedings of the National Academy of Sciences, the team led
by neuroscientist Solomon H. Snyder, M.D., has also pinpointed the neurotransmitter's
source -- itself a biologically unusual enzyme -- whose novelty as a drug target
"could put researchers on a royal road to stroke treatment."

The neurotransmitter is an amino acid called D-serine. It's odd, Snyder says, because
it differs in structure from any known molecule in its class found in mammals and other
higher animals. D-serine is what chemists call a right handed amino acid. Normally, amino
acids have atoms that extend from the left side of the molecule. These L-amino acids, as
they're called, are the rule in vertebrates, whose biochemistry is set up to deal with
these forms.

Some primitive organisms, however, notably bacteria, have a mixture of both L-amino
acids and their mirror images called D-amino acids. But to find a D-amino acid in humans,
Snyder says, "is unprecedented;" it's the equivalent of finding a Pterodactyl in
your local pet shop.

Moreover, unlike dopamine, serotonin or other traditional nerve transmitters, D-serine
isn't secreted at nerve cell endings in the brain. Instead, it comes from adjacent cells
called astrocytes, which enclose nerve cells in the brain's gray matter like a glove.

The current study adds conclusive evidence to the idea that D-serine -- released from
astrocytes -- activates receptors on key nerve cells in the brain. Activating these
receptors, called NMDA receptors, has long been linked with learning, memory and higher
thought. NMDA receptors are also known culprits in stroke damage in the brain, and have
become a focus for anti-stroke research.

A body of work at Hopkins in the last five years has pointed to D-serine's role, but
the new study, in which researchers have isolated and cloned the enzyme that makes
D-serine, shores it up. The enzyme, serine racemase, is as unusual as its product in that
it forms D-serine from L forms already in cells. "No other mammalian enzyme behaves
like it," Snyder says. The oddity of having an enzyme that converts amino acids from
a left to a right-handed form makes it an ideal drug target, he adds.

It invites hope that drugs inhibiting serine racemase in a timely way could damp down
production of D-serine and thus squelch activity at NMDA receptors. This would be useful,
during a stoke, Snyder says, when lack of oxygen in tissues triggers reactions that
greatly overstimulate the NMDA receptor. Overstimulation triggers reactions that destroy
nerve cells. "Being able to turn off or turn down the receptors might prevent
damage," he adds.

In this study, when the scientists added L-serine to cells artificially constructed to
contain the racemase enzyme, most of the L-serine was transformed to its D-serine twin.
The researchers also found D-serine and serine racemase concentrated in astrocytes
adjacent to NMDA receptors, but less common or nonexistent in other neural tissues.

For years, neuroscientists assumed that NMDA receptors could only be stimulated by a
single neurotransmitter, an amino acid called glutamate. They now know that two
neurotransmitters are needed to stimulate the receptors. D-serine was recently proposed by
the Hopkins scientists as the second, largely because microscope images of tagged D-serine
show it's physically near NMDA receptors in the synapse. Also, knocking D-serine out with
enzymes quickly stops NMDA receptors from being active.

Hopkins researchers aren't clear why nature would have such a bizarre and highly
specific neurotransmitter as D-serine, but Snyder suggests it may be because having two
neurotransmitters required to trigger the NMDA receptor may be a natural fail-safe
mechanism, like having two keys to the start button for a nuclear device.

"The NMDA receptor is so delicate, so crucial to us that some safeguards are in
order," says Snyder. "Get too much glutamate -- one of the most abundant
chemicals in the body -- and you're in trouble. But having a highly specific process to
make one of the neurotransmitters could insure that activating a receptor doesn't happen
by accident. The path to D-serine is pretty selective."

Other researchers in the study are Herman Wolosker, M.D., Ph.D., and Seth Blackshaw,
Ph.D. The work was supported by a U.S. Public Health Service grant and a grant of the
Theodore and Vada Stanley Foundation.

Under the terms of a licensing agreement between the Johns Hopkins University and
Guilford Pharmaceuticals, Inc., Dr. Snyder is entitled to a share of royalty received by
the University on sales of products related to the technology described in this release.
The University owns stock in Guilford, with Dr. Snyder having an interest in the
University share under University policy. The University's stock is subject to certain
restrictions under University policy. Dr. Snyder serves on the Board of Directors and the
Scientific Advisory Board of Guilford, he is a consultant to the company, and he owns
additional equity in Guilford. This arrangement is being managed by the University in
accordance with its conflict of interest policies

This article, titled "Serine racemase: A Glial enzyme synthesizing D-serine to
regulate glutamate-N-methyl-D-aspartate neurotransmission," is in the November issue
of The Proceedings of the National Academy of Sciences, issue 23, volume 96, pages
13409-13414.